Indolo[2,3-b]quinoxaline derivatives

ABSTRACT

Indolo[2,3-b]quinoxaline derivatives represented by the following formula: ##STR1## wherein one of R 1  and R 2  is a hydrogen atom and the other is a group of the formula: 
     
         --CH.sub.2 NHCCH.sub.3 (CH.sub.2 OH).sub.2, 
    
     etc, and R 3  is a hydrogen atom, a methyl group, etc.; and pharmaceutically acceptable salts thereof have an antitumor activity and are useful as medicines.

This is a national stage application, filed under 37 C.F.R. 1.371 ofPCT/JP94/00673, filed Apr. 22, 1994 and published as WO94/24135 Oct. 27,1994.

TECHNICAL FIELD

The present invention relates to indolo[2,3-b]quinoxaline derivatives,and more particularly to novel indolo[2,3-b]quinoxaline derivatives andpharmaceutically acceptable salts having an antitumor activity.

BACKGROUND ART

Among known compounds having an indolo[2,3-b]quinoxaline ring with anantitumor activity are two kinds of the compounds reported in JapanesePatent Laid-open No. 63-502587 and ibid. 63-502588.

However, the antitumor effect of these compounds is insufficient.

Accordingly, an object of the present invention is to provide novelindolo[2,3-b]quinoxaline derivatives having an excellent antitumoractivity.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provideindolo[2,3-b]quinoxaline derivatives represented by Formula (I):##STR2## wherein

one of R¹ and R² is a hydrogen atom and the other is a group representedby Formula (II): ##STR3## wherein R⁴ is a hydrogen atom or a methylgroup, R⁵, R⁶ and R⁷ are the same or different, and are each a hydrogenatom, a straight or branched lower alkyl group or a group represented byFormula (III):

    --CH.sub.2 --OX                                            (III)

wherein X is a hydrogen atom, a straight or branched lower alkyl groupor an acetyl group; and

R³ is a hydrogen atom, a methyl group or a group represented by Formula(IV):

    --(CH.sub.2).sub.m --P--(CH.sub.2).sub.n --Q               (IV)

wherein m is 1, 2 or 3, n is 1 or 2, P is an oxygen atom or a sulfuratom, and Q is a hydrogen atom, a hydroxyl group, a methoxy group, anethoxy group, an acetoxy group or an acetamido group;

or pharmaceutically acceptable salts thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

In the definitions of Formula (I), the straight or branched lower alkylgroup for R⁵, R⁶, R⁷ or X refers to a C₁ -C₆ lower alkyl group such as,for example, a methyl group, an ethyl group, a propyl group, a butylgroup, an isobutyl group, a pentyl group or a hexyl group.

The pharmaceutically acceptable salts of the indolo[2,3-b]quinoxalinederivative of Formula (I) refer to acid addition salts, which are thosegiven by addition of a pharmacologically acceptable acid to the nitrogenatom in the molecule of the compound of Formula (I), and examplesthereof are salts with mineral acids (e.g. hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid orphosphoric acid), and salts with organic acids (e.g. acetic acid, oxalicacid, citric acid, tartaric acid, maleic acid, succinic acid, fumaricacid, p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonicacid).

The indolo[2,3-b]quinoxaline derivatives of Formula (I) and thepharmaceutically acceptable salts thereof of the present invention canbe prepared by reacting an intermediate of Formula (XII): ##STR4##wherein one of R¹³ and R¹⁴ is a hydrogen atom and the other is a formylgroup, a chloromethyl group or a bromomethyl group, and R³ is as definedabove, with an amine compound represented by Formula (XV): ##STR5##wherein R⁴ is a hydrogen atom or a methyl group, and R⁵, R⁶ and R⁷ arethe same or different and are each a hydrogen atom, a straight orbranched lower alkyl group, or a group represented by Formula (III):

    --CH.sub.2 --OX                                            (III)

wherein X is a hydrogen atom, a straight or branched lower alkyl groupor an acetyl group.

More specifically, the intermediate of Formula (XII) wherein one of R¹³and R¹⁴ is a hydrogen atom and the other is a formyl group and the aminecompound of Formula (XV) are heated to form an imino compound, which isthen reduced with sodium borohydride or an alkoxy borohydride underheating to give a compound of Formula (I) as a salt-free form.

Furthermore, the intermediate of Formula (XII) wherein one of R¹³ andR¹⁴ is a hydrogen atom and the other is a chloromethyl group or abromomethyl group is reacted with the amine compound of Formula (XV)under heating to give a compound of Formula (I) as a salt-free form.

An acid addition salt of the compound of Formula (I) can be obtained bytreating the compound of Formula (I) with an acid such as hydrochloricacid. The acid addition salt is treated with an alkali compound toconvert into a compound as a free form.

The intermediate of Formula (XII) can be prepared by the methods shownin the following Reaction Scheme 1, 2 or 3. ##STR6##

In the 1,2-phenylenediamine compound of Formula (V), R⁸ is a hydrogenatom or a group represented by Formula (VI):

    --COOR.sup.9                                               (VI)

wherein R⁹ is a hydrogen atom or a lower alkyl group. The lower alkylgroup for R⁹ refers to a C₁ -C₆ lower alkyl group, for example, such asa methyl group, an ethyl group, a propyl group, a butyl group, anisobutyl group, a pentyl group or a hexyl group. When R⁸ in the compoundof Formula (V) is a hydrogen atom, R¹⁰ in the isatin compound of Formula(VII) is the group of Formula (VI), and when R⁸ is the group of Formula(VI), R¹⁰ is a hydrogen atom.

The 1,2-phenylenediamine compound of Formula (V) is condensed with theisatin compound of Formula (VII) in an organic acid such as acetic acidwith heating to give a heterocycle compound of Formula (VIII). Asclarified in the above definitions for the compound of Formula (VIII),one of R⁸ and R¹⁰ is a hydrogen atom and the other is the group ofFormula (VI).

The heterocycle compound of Formula (VIII) is, if desired, reacted witha methyl halide (e.g. methyl iodide), dimethyl sulfate or a compound ofFormula (IX) in the presence of sodium hydride in an aprotic polarsolvent such as dimethyl sulfoxide to give a compound of Formula (X). InFormula (IX), m is 1, 2 or 3, n is 1 or 2, P is an oxygen atom or asulfur atom, Q is a hydrogen atom, a hydroxyl group, a methoxy group, anethoxy group, an acetoxy group or an acetamido group, and Y is a halogenatom, a mesyloxy group, a benzenesulfonyloxy group or ap-toluenesulfonyloxy group.

Subsequently, the heterocycle compound of Formula (VIII) or the compoundof Formula (X) is reduced with lithium aluminum hydride or an alkoxylithium aluminum hydride in an aprotic polar solvent such astetrahydrofuran to convert the group of Formula (VI) defined for R⁸ orR⁹ in the compound of Formula (VIII) or (X) into a hydroxymethyl group,thereby giving a compound of Formula (XI). Reduction of the compound ofFormula (VIII) gives a compound of Formula (XI) wherein R³ is a hydrogenatom, and reduction of the compound of Formula (X) gives a compound ofFormula (XI) wherein R³ is a methyl group or a group of Formula (IV):

    --(CH.sub.2).sub.m --P--(CH.sub.2).sub.n --Q--             (IV)

wherein m, n, P and Q are as defined above.

The compound of Formula (XI) is oxidized with manganese dioxide in anorganic solvent such as dioxane, tetrahydrofuran, carbon tetrachloride,chloroform or methylene chloride to convert the hydroxymethyl groupdefined for one of R¹¹ and R¹² in Formula (XI) into a formyl group,thereby giving an intermediate of Formula (XII).

Furthermore, the compound represented by Formula (XI) is halogenatedwith thionyl chloride or thionyl bromide in an organic solvent such ascarbon tetrachloride, chloroform or methylene chloride to convert thehydroxymethyl group into a chloromethyl group or bromomethyl group,respectively, thereby giving an intermediate of Formula (XII). ##STR7##

In the 1,2-phenylenediamine compound of Formula (V'), R¹⁵ is a hydrogenatom or a methyl group.

When R¹⁵ in Formula (V') is a hydrogen atom, R¹⁶ in the isatin compoundof Formula (VII') is a methyl group, and when R¹⁵ is a methyl group, R¹⁶is a hydrogen atom.

The 1,2-phenylenediamine compound of Formula (V') is reacted with theisatin compound of Formula (VII') by a method similar to that shown inReaction Scheme 1 to give a corresponding heterocycle compound ofFormula (VIII'), which is then reacted by a method similar to that shownin Reaction Scheme 1 to give a compound of Formula (X').

The compound of Formula (VIII') or (X') wherein one of R¹⁵ and R¹⁶ is ahydrogen atom and the other is a methyl group is oxidized with, forexample, chromic acid and then hydrolyzed to convert the methyl groupfor R¹⁵ and R¹⁶ into a formyl group, thereby giving an intermediate ofFormula (XII). ##STR8##

In the 1,2-phenylenediamine compound of Formula (V"), R¹⁷ is a hydrogenatom or a halogen atom which is a chlorine atom or a bromine atom.

When R¹⁷ in Formula (V") is a hydrogen atom, R¹⁸ in the isatin compoundof Formula (VII") is a chlorine atom or a bromine atom, and when R¹⁷ isa chlorine atom or a bromine atom, R¹⁸ is a hydrogen atom.

The 1,2-phenylenediamine compound of Formula (V") is reacted with theisatin compound of Formula (VII") by a method similar to that shown inReaction Scheme 1 to give compounds of Formulae (VIII") and (X"),successively.

The compound of Formula (VIII") or (X") wherein one of R¹⁷ and R¹⁸ is ahydrogen atom and the other is a chlorine atom or a bromine atom istreated with copper cyanide to convert the halogen atom for R¹⁷ or R¹⁸into a nitrile group, thereby giving a compound of Formula (X"'). InFormula (X"'), one of R²⁰ and R²¹ is a hydrogen atom and the another isa nitrile group.

The compound of Formula (X"') wherein one of R²⁰ and R²¹ is a hydrogenatom and the other is a nitrile group is reduced with lithium aluminumhydride, an alkoxy lithium aluminum hydride or an alkyl aluminum hydridein an organic solvent such as toluene, benzene or methylene chloride togive an intermediate (formyl form) of Formula (XII) wherein one of R¹³and R¹⁴ is a hydrogen atom and the other is a formyl group.

An intermediate (halomethyl form) of Formula (XII) wherein one of R¹³and R¹⁴ is a hydrogen atom and the other is a chloromethyl group or abromomethyl group can be prepared by reducing the above intermediate(formyl form) of Formula (XII) with, for example, lithium aluminumhydride to give a compound of Formula (XI) shown in Reaction Scheme 1,followed by halogenation of the compound of Formula (XI) with thionylchloride or thionyl bromide by a method similar to that shown inReaction Scheme 1. In Reaction Scheme 3, the compound of Formula (IX) isas defined above, and Z defined for Formulae (X") and (X"') and R³defined for Formula (XII) are as defined above.

The indolo[2,3-b]quinoxaline derivatives of Formula (I) andpharmaceutically acceptable salts of the present invention have a potentantitumor activity, and therefore they are useful as medicines.

The indolo[2,3-b]quinoxaline derivatives of Formula (I) andpharmaceutically acceptable salts of the present invention can beadministered orally or parenterally in a conventional dosage form.Examples of the form are tablets, powders, granules, dusts, capsules,solutions, emulsions, suspensions and injections, and all of which canbe prepared by conventional practices. When used for humans, the dosemay be different depending on the age, body weight, symptoms, route ofadministration and frequency of administration, but it is usually from 1to 1000 mg per day.

The present invention is illustrated in more detail by the followingReference Examples, Examples and an Experiment.

EXAMPLE 1 Preparation of2-methyl-2-(((6-methyl-indolo[2,3-b]quinoxalin-4-yl)methyl)amino)1,3-propanediolHydrochloride

(1) Preparations of methyl 4-indolo[2,3-b]quinoxalinecarboxylate andmethyl 1-indolo[2,3-b]quinoxalinecarboxylate

A suspension of 20 g of methyl 2,3-diaminobenzoate and 17.7 g of isatinin 230 ml of acetic acid was heated under reflux for an hour. Aftercompletion of the reaction, the reaction solution was allowed to standat room temperature overnight, and the resulting precipitate wascollected by filtration. The precipitate was purified by silica gelcolumn chromatography to give methyl4-indolo[2,3-b]quinoxalinecarboxylate and methyl1-indolo[2,3-b]quinoxalinecarboxylate.

Methyl 4-indolo[2,3-b]quinoxalinecarboxylate m.p. 278°-280° C. Yield13.47 g

Methyl 1-indolo[2,3-b]quinoxalinecarboxylate m.p. 242°-244° C. Yield2.08 g.

(2) Preparation of methyl 6-methyl-4-indolo[2,3-b]quinoxalinecarboxylate

To a solution of 4.30 g (15.5 mmol) of methyl4-indolo[2,3-b]quinoxalinecarboxylate obtained in the above item (1) indimethyl sulfoxide was added 0.81 g (18.6 mmol, 1.2 eq.) of sodiumhydride, followed by stirring at room temperature. One hour later, 1.57ml (18.6 mmol, 1.2 eq.) of methyl iodide was added, followed by stirringfor a further 90 minutes. After addition of water to the mixture, theresulting precipitate was collected by filtration, and recrystallizedfrom ethyl acetate--ether--n-hexane to give methyl6-methyl-4-indolo[2,3-b]quinoxalinecarboxylate.

m.p. 155°-157° C. Yield 3.86 g.

(3) Preparation of 4-hydroxymethyl-6-methyl-indolo[2,3-b]quinoxaline

To a solution of 3.46 g (11.9 mmol) of methyl6-methyl-4-indolo[2,3-b]quinoxalinecarboxylate obtained in the aboveitem (2) in 120 ml of tetrahydrofuran was added 0.54 g (14.3 mmol, 1.2mol eq.) of lithium aluminum hydride under ice-cooling, followed bystirring for an hour. 10 ml of ethyl acetate, 10 ml of water and 10 mlof 5% sodium hydroxide were added successively, and the resultingprecipitate was collected by filtration. The precipitate was dissolvedin a mixture of 1N hydrochloric acid and chloroform, and the organiclayer was separated, combined with the filtrate, washed with an aqueoussodium chloride solution and dried over magnesium sulfate. Afterevaporation of the solvent, the residue was recrystallized frommethylene chloride--methanol--n-hexane to give4-hydroxymethyl-6-methylindolo[2,3-b]quinoxaline.

m.p. 201° C. Yield 2.88 g.

(4) Preparation of 6-methyl-4-indolo[2,3-b]quinoxalinealdehyde

To a solution of 2.36 g (9.0 mmol) of4-hydroxymethyl-6-methylindolo[2,3-b]quinoxaline obtained in the aboveitem (3) in 200 ml of methylene chloride was added 11.87 g (134 mmol, 15eq.) of activated manganese dioxide, followed by stirring at roomtemperature for 8 hours. The excess manganese dioxide was filtered offthrough Celite, the filtrate was concentrated and purified by silica gelcolumn chromatography (AcOEt: CHCl₃ =1:9) to give6-methyl-4-indolo[2,3-b]quinoxalinealdehyde.

m.p. 219°-221° C. Yield 1.84 g

(5) Preparation of2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-4-yl)methyl)amino)-1,3-propanediol

A suspension of 0.26 g of 6-methyl-4-indolo[2,3-b]quinoxalinealdehydeobtained in the above item (4), 0.52 g of2-amino-2-methyl-1,3-propanediolamine and 0.28 g of p-toluenesulfonicacid in toluene was heated under reflux. After evaporation of thesolvent, 0.075 g of sodium borohydride and 30 ml of ethanol were addedto the residue, followed by stirring at room temperature. Afterevaporation of the solvent, the residue was purified by silica gelcolumn chromatography (MeOH: CHCl₃ =1:9), followed by addition of 4Nhydrogen chloride--ethyl acetate solution. The excess hydrogenchloride--ethyl acetate solution was evaporated under reduced pressureto give2-methyl-2-(((6-methylindolo-[2,3-b]quinoxalin-4-yl)methyl)amino)-1,3-propanediolhydrochloride.

m.p. 278°-279° C. Yield 0.19 g.

EXAMPLE 2 Preparation of2-methyl-2-(((6-methylindolo-[2,3-b]quinoxalin-1-yl)methyl)amino)-1,3-propanediolHydrochloride

(1) Preparation of methyl 6-methyl-1-indolo[2,3-b]quinoxalinecarboxylate

Methyl 1-indolo[2,3-b]quinoxalinecarboxylate obtained in Example 1(1)was treated by a method similar to that of Example 1(2) to give methyl6-methyl-1-indolo[2,3-b]quinoxalinecarboxylate.

m.p. 194°-196° C.

(2) Preparation of 1-hydroxymethyl-6-methylindolo[2,3-b]quinoxaline

Methyl 6-methyl-1-indolo[2,3-b]quinoxalinecarboxylate was treated by amethod similar to that of Example 1(3) to give1-hydroxymethyl-6-methylindolo[2,3-b]quinoxaline.

m.p. 191°-194° C.

(3) Preparation of 6-methyl-1-indolo[2,3-b]quinoxalinealdehyde

1-Hydroxymethyl-6-methylindolo[2,3-b]quinoxaline was treated by a methodsimilar to that of Example 1(4) to give6-methyl-1-indolo[2,3-b]quinoxalinealdehyde.

m.p. 257.5°-258° C.

(4) Preparation of2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-1-yl)methyl)amino)-1,3-propanediol

6-Methyl-1-indolo[2,3-b]quinoxalinealdehyde was treated by a methodsimilar to that of Example 1(5) to give2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-1-yl)methyl)amino)-1,3-propanediolhydrochloride.

m.p. 263°-265° C. (decomposition).

EXAMPLE 3 Preparation of2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-7-yl)methyl)amino)-1,3-propanediolHydrochloride

(1) Preparation of methyl 7-indolo[2,3-b]quinoxalinecarboxylate

A suspension of 3.96 g of 1,2-phenylenediamine and 7.00 g of7-isatincarboxylic acid in 70 ml of acetic acid was heated under refluxfor an hour. After completion of the reaction, the reaction solution wasallowed to cool to room temperature, followed by addition of water, andresulting precipitate was collected by filtration. The thus obtained7-indolo[2,3-b]quinolinecarboxylic acid and 170 ml of thionyl chloridewere refluxed for 2 hours, and the excess thionyl chloride wasevaporated. The residue, after addition of 250 ml of methanol, wasstirred overnight. After addition of water, the resulting precipitatewas collected by filtration, and purified by silica gel columnchromatography to give methyl 7-indolo[2,3-b]quinoxalinecarboxylate.

m.p. 251°-255° C. Yield 4.04 g.

(2) Preparation of methyl 6-methyl-7-indolo[2,3-b]quinoxalinecarboxylate

Methyl 7-indolo[2,3-b]quinoxalinecarboxylate was treated by a methodsimilar to that of Example 1(2) to give methyl6-methyl-7-indolo[2,3-b]quinoxalinecarboxylate.

m.p. 184°-186° C.

(3) Preparation of 7-hydroxymethyl-6-methylindolo[2,3-b]quinoxaline

Methyl 6-methyl-7-indolo[2,3-b]quinoxalinecarboxylate was treated by amethod similar to that of Example 1(3) to give7-hydroxymethyl-6-methylindolo[2,3-b]quinoxaline.

m.p. 237°-238° C.

(4) Preparation of 6-methyl-7-indolo[2,3-b]quinoxalinealdehyde

7-Hydroxymethyl-6-methylindolo[2,3-b]quinoxaline was treated by a methodsimilar to that of Example 1(4) to give6-methyl-7-indolo[2,3-b]quinoxalinealdehyde.

m.p. 220° C.

(5) Preparation of2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-7-yl)methyl)amino)-1,3-propanediol

6-Methyl-7-indolo[2,3-b]quinoxalinealdehyde was treated by a methodsimilar to that of Example 1(5) to give2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-7-yl)methyl)amino)-1,3-propanediolhydrochloride.

m.p. 284°-286° C.

EXAMPLE 4 Preparation of2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-9-yl)methyl)amino)-1,3-propanediolHydrochloride

(1) Preparation of 9-methylindolo[2,3,b]quinoxaline

A suspension of 4.33 g of 1,2-phenylenediamine and 6.45 g of5-methylisatin in 500 ml of acetic acid was refluxed for 2 hours. To thereaction solution was added 50 ml of water, and the precipitate wascollected by filtration, dried and recrystallized fromchloroform--ethanol--tetrahydrofuran to give9-methylindolo-[2,3,-b]quinoxaline.

m.p. 299°-300° C. Yield 4.20 g.

(2) Preparation of 6,9-dimethylindolo[2,3-b]quinoxaline

9-Methylindolo[2,3-b]quinoxaline was treated by a method similar to thatof Example 1(2) to give 6,9-dimethylindolo[2,3-b]quinoxaline.

m.p. 163°-164° C.

(3) Preparation of 9-diacetoxymethyl-6-methylindolo[2,3-b]quinoxaline

To a solution of 5.50 g of 6,9-dimethylindolo[2,3-b]quinoxaline in 25 mlof acetic anhydride was added 4.5 ml of conc. sulfuric acid underice-cooling, followed by adding dropwise a solution of 6.24 g of chromicanhydride in 28 ml of acetic anhydride at 10° C. or below, and themixture was stirred for 40 minutes. The reaction solution was pouredinto 300 ml of ice water, and extracted twice with 200 ml of chloroform.The combined organic layer was washed with an aqueous sodium chloridesolution and dried over anhydrous sodium sulfate. After evaporation ofthe solvent under reduced pressure, the residue was treated by silicagel column chromatography (chloroform), and the resulting fractions wererecrystallized from chloroform--ethanol to give 1.32 g of9-diacetoxy-methyl-6-methylindolo[2,3-b]quinoxaline.

m.p. 220°-224° C.

(4) Preparation of 6-methyl-9-indolo[2,3-b]quinoxalinealdehyde

To a suspension of 1.29 g of9-diacetoxy-methyl-6-methylindolo[2,3-b]-quinoxaline in 50 ml oftetrahydrofuran were added 1 ml of water and 1 ml of conc. sulfuricacid, followed by reflux for 5 hours. The reaction solution was allowedto stand overnight, and the resulting crystals were collected byfiltration to give 0.78 g of6-methyl-9-indolo[2,3-b]quinoxalinealdehyde.

m.p. 228°-230° C.

(5) Preparation of2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-9-yl)methyl)amino)-1,3-propanediol

6-Methyl-9-indolo[2,3-b]quinoxalinealdehyde was treated by a methodsimilar to that of Example 1(5) to give2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-9-yl)methyl)amino)-1,3-propanediolhydrochloride.

m.p. 200°-202° C.

EXAMPLE 5

Preparation of2-(((6-methylindolo[2,3-b]quinoxalin-4-yl)methyl)amino)-1,3-propanediolHydrochloride

(1) Preparation of 4-chloromethyl-6-methylindolo[2,3-b]quinoxaline

To a solution of 304 mg (1.16 mmol) of4-hydroxymethyl-6-methylindolo[2,3-b]quinoxaline in 30 ml of methylenechloride was added 0.126 ml (1.73 mmol, 1.5 eq.) of thionyl chlorideunder ice-cooling, followed by stirring for 3 hours. The reactionsolution was poured into 50 ml of ice water, and extracted withmethylene chloride. The organic layer was washed 3 times with asaturated aqueous sodium hydrogen carbonate solution and dried overanhydrous sodium sulfate. Evaporation of the solvent gave 335 mg of thecrude product 4-chloromethyl-6-methylindolo[2,3-b]quinoxaline, which wasused for the next reaction without further purification.

m.p. 204°-206° C.

(2) Preparation of2-(((6-methylindolo[2,3-b]quinoxalin-4-yl)methyl)amino)-1,3-propanediol

A mixture of 286 mg of the crude product4-chloromethyl-6-methylindolo[2,3-b]quinoxaline obtained in the aboveitem (1) and 4,629 g (50.8 mmol) of 2-amino-1,3 propanediol was heatedat 150° C. for 10% minutes. To the cooled reaction solution were added10 methanol--methylene chloride and water, and the organic layer wasseparated. The aqueous layer was further extracted 4 times with 10%methanol--methylene chloride, and the combined organic layer was driedover anhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (MeOH: CHCl₃=1:10). To the fractions was added 4N hydrogen chloride--ethyl acetatesolution, and the excess hydrogen chloride--ethyl acetate solution wasevaporated under reduced pressure to give the hydrochloride, which wasthen recrystallized from ethanol to give2-(((6-methylindolo[2,3-b]quinoxalin-4-yl)methyl)amino)-1,3-propanediolhydrochloride.

m.p. 247°-249° C. Yield 239 mg.

EXAMPLE 6 Preparation of a mixture of2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-2-yl)methyl)amino)-1,3-propanediolhydrochloride and2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-3-yl)methyl)amino)-1,3-propanediolHydrochloride

(1) Preparation of a mixture of 2-cyano-6-methylindolo[2,3-b]quinoxalineand 3-cyano-6-methylindolo[2,3-b]quinoxaline

A solution of 2.66 g (20 mmol) of 3,4-diaminobenzonitrile and 3.22 g(1.0 eq.) of 1-methylisatin in 25 ml of acetic acid was refluxed for 2hours. The reaction solution was allowed to stand at room temperature,and the resulting crystals were collected by filtration andrecrystallized from chloroform--ethanol to give a mixture of2-cyano-6-methylindolo[2,3-b]quinoxaline and3-cyano-6-methylindolo[2,3-b]quinoxaline.

m.p. 237°-246° C. Yield 4.03 g.

(2) Preparation of a mixture of6-methyl-2-indolo[2,3-b]quinoxalinealdehyde and6-methyl-3-indolo[2,3-b]quinoxalinealdehyde

To a solution of 1.70 g (6.58 mmol) of the mixture obtained in the aboveitem (1) in 300 ml of toluene was added a solution of 7.6 ml ofdiisobutyl aluminum hydride in 1.02 mol/l of toluene under a nitrogenstream at room temperature, and the stirring was continued for 2 hours.2 ml of ethyl acetate was added to the reaction solution, followed bystirring for a further one hour to complete the reaction. After additionof water and dilute hydrochloric acid to the reaction solution, themixture was extracted twice with chloroform, and the combined extractwas washed with an aqueous sodium chloride solution and dried oversodium sulfate. The solvent was evaporated, and the residue wassubjected to silica gel column chromatography (MeOH: CHCl₃ =0.1:10), andthe resulting fractions were recrystallized from chloroform--ethanol togive a mixture of 6-methyl-2-indolo[2,3-b]quinoxalinealdehyde and6-methyl-3-indolo[2,3-b]quinoxalinealdehyde.

m.p. 214°-219° C. Yield 1.02 g.

(3) Synthesis of a mixture of2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-2-yl)methyl)amino)-1,3-propanedioland2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-3-yl)methyl)amino)-1,3-propanediol

The mixture obtained in the above item (2) was treated by a methodsimilar to that of Example 1(5) to give a mixture of2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-2-yl)methyl)amino)-1,3-propanediolhydrochloride and2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-3-yl)methyl)amino)-1,3-propanediolhydrochloride.

m.p. 243°-248° C. (decomposition).

EXAMPLE 7 Preparation of2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-8-yl)methyl)amino)-1,3-propanediolHydrochloride

(1) Preparation of 8-bromoindolo[2,3-b]quinoxaline

A solution of 15.18 g (67.2 mmol) of 6-bromoisatin and 7.26 g (1.0 eq.)of 1,2-phenylenediamine in 250 ml of butyric acid was refluxed for 4hours, followed by allowing to stand at room temperature for 16 hours.The precipitate was collected by filtration to give8-bromoindolo[2,3-b]quinoxaline.

m.p. >300° C. Yield 17.60 g.

(2) Preparation of 8-bromo-6-methylindolo[2,3-b]quinoxaline

8-Bromoindolo[2,3-b]quinoxaline obtained in the above item (1) wastreated by a method similar to that of Example 1 to give8-bromo-6-methylindolo[2,3-b]quinoxaline.

m.p. 182°-183° C.

(3) Preparation of 8-cyano-6-methylindolo[2,3-b]quinoxaline

To 8.00 g (25.6 mmol) of 8-bromo-6-methylindolo[2,3-b]quinoxalineobtained in the above item (2) were added 8.00 g of copper cyanide, 35ml of dimethyl sulfoxide and 3.8 ml of pyridine, followed by reflux foran hour. The reaction solution, while hot, was poured into icewater--chloroform with stirring, and extracted with chloroform. Theextract was evaporated to dryness under reduced pressure, the residuewas subjected to silica gel column chromatography (chloroform), and theresulting fractions were recrystallized from chloroform--ethanol to give8-cyano-6-methylindolo[2,3-b]quinoxaline.

m.p. 284°-287° C. Yield 1.96 g.

(4) Preparation of 6-methyl-8-indolo[2,3-b]quinoxalinealdehyde

8-Cyano-6-methylindolo[2,3-b]quinoxaline obtained in the above item (3)was treated by a method similar to that of Example 6(4) to give6-methyl-8-indolo[2,3- b]quinoxalinealdehyde.

m.p. 237°-238° C.

(5) Preparation of2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-8-yl)methyl)amino)-1,3-propanediol

6-Methyl-8-indolo[2,3-b]quinoxalinealdehyde obtained in the above item(4) was treated by a method similar to that of Example 1 (5) to give2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-8-yl)methyl)amino)-1,3-propanediolhydrochloride.

m.p. 273°-275° C. (decomposition).

EXAMPLE 8 Preparation of2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-10-yl)methyl)amino)-1,3-propanediolHydrochloride

(1) Preparation of 10-bromoindolo[2,3-b]quinoxaline

A solution of 3.40 g (15.0 mmol) of 4-bromoisatin and 1.63 g (1 eq.) of1,2-phenylenediamine in 50 ml of acetic acid was refluxed for 2 hours.The reaction solution was allowed to stand at room temperature for 16hours, and the resulting precipitate was collected by filtration to give10-bromoindolo[2,3-b]quinoxaline.

m.p. >300° C. Yield 1.82 g.

(2) Preparation of 10-bromo-6-methylindolo[2,3-b]quinoxaline

10-Bromoindolo[2,3-b]quinoxaline obtained in the above item (1) wastreated by a method similar to that of Example 1(2) to give10-bromo-6-methylindolo[2,3-b]quinoxaline.

m.p. 208°-209° C.

(3) Preparation of 10-cyano-6-methylindolo[2,3-b]quinoxaline

To 15.14 g of 10-bromo-6-methylindolo[2,3-b]quinoxaline obtained in theabove item (2) were added 8.02 g of copper cyanide, 67 ml of dimethylsulfoxide and 7.1 ml of pyridine, followed by heating at 180° C. withstirring for 40 minutes. Then, the mixture was worked up by a methodsimilar to that of Example 7(3) to give10-cyano-6-methylindolo[2,3-b]quinoxaline.

m.p. 237°-239°0 C. Yield 10.03 g.

(4) Preparation of 6-methyl-10-indolo[2,3-b]quinoxalinealdehyde

10-Cyano-6-methylindolo[2,3-b]quinoxaline obtained in the above item (3)was treated by a method similar to that of Example 6(2) to give6-methylindolo[2,3-b]quinoxalinealdehyde.

m.p. 219°-220° C.

(5) Preparation of2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-10-yl)methyl)amino)-1,3-propanediol

6-Methyl-10-indolo[2,3-b]quinoxalinealdehyde obtained in the above item(4) was treated by a method similar to that of Example 1(5) to give2-methyl-2-(((6-methylindolo[2,3-b]quinoxalin-10-yl)methyl)amino)-1,3-propanediolhydrochloride.

m.p. 250°-252° C. (decomposition).

Experiment P388 Lymphocytic Leukemia Test

(1) Test animal

Female, CDF1 mice were intraperitoneally transplanted with each of 1×10⁶cells of P388 lymphocytic leukemia passaged on female, DBA/2 mice. Thetransplantation day refers to day 0.

(2) Administration route

A suspension of the test drug in 0.5% of gum arabic/saline solution wasadministered intraperitoneally once a day, 5 times in all, from day 1 today 5. A solution of 5-fluorouracil in saline served as a comparativedrug, and similarly administered. Control group were similarlyadministered with only 0.5% gum arabic/saline solution. Eight animalswere used for the treated group with the test drugs and the comparativedrug, respectively, and 16 animals for control group.

(3) Evaluation method

Effect evaluation was carried out according to the criterion [VendittiJM, Wesley RA, Plowman J, Adv. Pharmacol. Chemother., 20: lp (1989)] ofthe National Cancer Institute of the United States (NCI).

The survivors of each group were recorded for 30 days, and the value ofT/C×100 (%) was calculated from the median survival times for thetreated animals (T) and the control animals(C).

When the T/C value is 125 or more, the drug is judged to be effective.

(4) Test results

The test results are shown in Table 1.

The compounds of the present invention indicated great value of T/C×100.

                  TABLE 1    ______________________________________    Effect against P388 in mouse    Test drug       dose (mg/kg)                               T/C × 100    ______________________________________    Compound obtained in                    100         58    Example 1       25         >306                    6.25       142    Compound obtained in                    25         169    Example 2       6.25       149    Compound obtained in                    100        127    Example 3       25         113                    6.25       101    5-fluorouracil  100        --                    25         176                    6.25       167    ______________________________________

Industrial Applicability

The indolo[2,3-b]quinoxaline derivatives and pharmaceutically acceptablesalts of the present invention have a potent antitumor activity, andtherefore they are useful as antitumor agents.

We claim:
 1. An indolo[2,3-b]quinoxaline derivative represented byFormula (I): ##STR9## wherein one of R¹ and R² is a hydrogen atom andthe other is a group represented by Formula (II): ##STR10## wherein R⁴is a hydrogen atom or a methyl group, R⁵, R⁶ and R⁷ are the same ordifferent, and are each a hydrogen atom, a straight or branched loweralkyl group or a group represented by Formula (III):

    --CH.sub.2 --OX                                            (III)

wherein X is a hydrogen atom, a straight or branched lower alkyl groupor an acetyl group; and R₃ is a hydrogen atom, a methyl group or a grouprepresented by Formula (IV):

    --(CH.sub.2).sub.m --P--(CH.sub.2).sub.n --Q               (IV)

wherein m is 1, 2 or 3, n is 1 or 2, P is an oxygen atom or a sulfuratom, and Q is a hydrogen atom, a hydroxyl group, a methoxy group, anethoxy group, an acetoxy group or an acetamido group; or apharmaceutically acceptable salt thereof.